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The Role of Nucleoporin Elys in Nuclear Pore Complex Assembly and Regulation of Genome Architecture

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The Role of Nucleoporin Elys in Nuclear Pore Complex Assembly and Regulation of Genome Architecture International Journal of Molecular Sciences Review The Role of Nucleoporin Elys in Nuclear Pore Complex Assembly and Regulation of Genome Architecture Yuri Y. Shevelyov Department of Molecular Genetics of Cell, Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; [email protected]; Tel.: +7-499-196-0809 Received: 29 November 2020; Accepted: 11 December 2020; Published: 13 December 2020 Abstract: For a long time, the nuclear lamina was thought to be the sole scaffold for the attachment of chromosomes to the nuclear envelope (NE) in metazoans. However, accumulating evidence indicates that nuclear pore complexes (NPCs) comprised of nucleoporins (Nups) participate in this process as well. One of the Nups, Elys, initiates NPC reassembly at the end of mitosis. Elys directly binds the decondensing chromatin and interacts with the Nup107–160 subcomplex of NPCs, thus serving as a seeding point for the subsequent recruitment of other NPC subcomplexes and connecting chromatin with the re-forming NE. Recent studies also uncovered the important functions of Elys during interphase where it interacts with chromatin and affects its compactness. Therefore, Elys seems to be one of the key Nups regulating chromatin organization. This review summarizes the current state of our knowledge about the participation of Elys in the post-mitotic NPC reassembly as well as the role that Elys and other Nups play in the maintenance of genome architecture. Keywords: nucleoporin; Elys; Mel-28; NPC; nuclear envelope; genome architecture; chromatin 1. Introduction In eukaryotic cells, the nuclear-cytoplasmic transport of macromolecules occurs through channels in the nuclear envelope (NE) formed by nuclear pore complexes (NPCs). NPCs are large multiprotein structures consisting of ~30 nucleoporins (Nups) each represented by 8–32 copies [1]. Apart from transport function, Nups interact with chromatin, thus affecting genome architecture and gene expression [2–18]. While in yeast, the recruitment of genes to the NPCs causes their activation and is accompanied by the emergence of transcriptional memory [19,20], in higher eukaryotes the picture is more complicated. In metazoans, some Nups are localized not only at the NE, but also in the nucleoplasm [21–23]. Moreover, while nucleoplasmic Nups bind to active genes promoting their transcription, the constituents of NPCs at the NE mostly interact with the silent genes, or those poised for activation [8–10,12,13,15–18]. In a similar fashion to yeast, the transcriptional memory was revealed in Drosophila and mammals. In mammals, this mechanism may be exemplified by the interaction of interferon-inducible genes with the nucleoplasmic Nups [24]. In contrast in Drosophila, ecdysone-inducible genes interact with the NPC-linked Nups [16]. Numerous data suggest that peripheral chromatin interacts with both components of the NE–the nuclear lamina (NL) and NPCs. The NL is a meshwork of lamins and lamin-associated proteins which lines the inner nuclear membrane [25]. A decade ago, lamina-associated chromosomal domains (LADs) were revealed in Drosophila, mammals and nematode [26–30]. It was shown that either artificial disruption or a naturally occurring reduction of specific components of the NL resulted in chromatin relocalization from the NE to the nuclear interior, thus indicating that peripheral chromatin is attached to the NL [31–42]. Int. J. Mol. Sci. 2020, 21, 9475; doi:10.3390/ijms21249475 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 9475 2 of 13 Several findings indicate that NPCs may also be involved in the anchorage of chromosomes to the NE. In C. elegans, the single X chromosome in males has a more peripheral position in the nucleus than the two X chromosomes in hermaphrodites and this spatial organization correlates with more pronounced interactions of the single X chromosome with one of the Nups [43]. Similarly, the single X chromosome in Drosophila SL-2 cells appears to be more strongly bound with Nups, such as Megator (Mtor) and Nup153, and is located closer to the NE than the autosomes. This proximal position of the X chromosome relative to the NE becomes more distal upon Nup153 depletion [10]. Furthermore, depletion of Nup153 in mouse embryonic stem cells (mESCs) leads to several Nup153-target loci being located further from the NE [14]. Additionally, depletion of Nup98 in Drosophila S2 cells results in the relocalization of two ecdysone-inducible genes from the NE to the nuclear interior [16]. Collectively, these findings support the model whereby the interactions of the genome not only with the NL, but also with the NPCs are important for determining the intranuclear positioning of chromosomes. The involvement of Nups in these interactions with chromatin arouses a particular interest in Elys (embryonic large molecule derived from yolk sac), also known as Mel-28 (maternal effect lethal-28) or AHCTF1 (AT-hook containing transcription factor 1), as the Nup that can bind chromatin directly. Although several recently published reviews have described participation of Nups in chromatin organization [44–47], these papers did not focus on Elys. Here, I discuss the role that Elys plays in the post-mitotic NPC reassembly and in establishing and maintenance of overall genome architecture. 2. Role of Elys in Post-Mitotic Reassembly of NPCs and Other NE Components Elys was initially identified as an AT-hook-containing transcription factor which is strongly expressed in embryonic hematopoietic tissues and more weakly in other mice tissues, localizing to both the nucleus and cytoplasm [48]. However, later studies did not support the presence of Elys in the cytoplasm. During interphase, Elys was shown to colocalize with the NPCs at the NE in different organisms including mammals, Xenopus, nematode and Drosophila [49–54] (Figure1a, left panel). Accordingly, Elys contains the N-terminal β-propeller and α-helical domains, which are both responsible for its association with the Nup107–160 subcomplex of NPC [55,56] (Figure1b). In addition to its localization at the NE, Elys is also diffusely distributed in the nuclear interior [51] concentrating in the dot-like structures known as GLFG bodies [21,23]. During mitosis, Elys is located at the surface of chromatin masses as well as residing at kinetochores and spindle poles [49–51,56,57] (Figure1a, right panel). In nematode and mammals, the localization of Elys at kinetochores is necessary for mitosis to proceed correctly [49–51]. However, in Drosophila, Elys was not observed to reside at the kinetochores [54]. Interestingly, the entire Nup107–160 subcomplex also resides at kinetochores during mitosis in mammals [58], but not in Drosophila [59]. Therefore, although it was not shown directly, Elys, together with the Nup107/160 subcomplex, seems to be dispensable for mitotic chromosome segregation in Drosophila. The process of NPC reassembly at the end of mitosis consists of sequential steps of recruitment of NPC subcomplexes to the re-forming NE. It is initiated in anaphase by Elys binding to the decondensing chromatin via the AT-hook and another C-terminal domain [60], followed by Elys-mediated recruitment of the Nup107–160 subcomplex of NPC [51,52,60–63] (Figure1c). Field emission scanning electron microscopy confirms the colocalization of Elys with the Nup107–160 subcomplex on chromatin “seeding” sites during NPC reassembly [64]. Consistent with Elys targeting of Nup107–160 subcomplex to chromatin, structural studies have shown that Elys is directly associated with the Nup160 subunit of this subcomplex [65,66]. During the next step of NPC reassembly, the transmembrane Nups such as Pom121 and NDC1, which are already integrated in the inner nuclear membrane, bind to the Nup107–160 subcomplex; together, this complex recruits other components of the NPC to this site [60,67,68]. Depletion of Elys results in the failure of NPCs to localize at the NE [50–52,63], thus indicating that Elys is strictly required for NPC reassembly at the end of mitosis. However, besides post-mitotic reassembly, NPCs may be incorporated in the NE during interphase via an Elys-independent pathway [63,69]. Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 13 Several findings indicate that NPCs may also be involved in the anchorage of chromosomes to the NE. In C. elegans, the single X chromosome in males has a more peripheral position in the nucleus than the two X chromosomes in hermaphrodites and this spatial organization correlates with more pronounced interactions of the single X chromosome with one of the Nups [43]. Similarly, the single X chromosome in Drosophila SL-2 cells appears to be more strongly bound with Nups, such as Megator (Mtor) and Nup153, and is located closer to the NE than the autosomes. This proximal position of the X chromosome relative to the NE becomes more distal upon Nup153 depletion [10]. Furthermore, depletion of Nup153 in mouse embryonic stem cells (mESCs) leads to several Nup153- target loci being located further from the NE [14]. Additionally, depletion of Nup98 in Drosophila S2 cells results in the relocalization of two ecdysone-inducible genes from the NE to the nuclear interior [16]. Collectively, these findings support the model whereby the interactions of the genome not only with the NL, but also with the NPCs are important for determining the intranuclear positioning of chromosomes. The involvement of Nups in these interactions with chromatin arouses a particular interest in Elys (embryonic large molecule derived from
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